Myelodysplastic Syndromes and Myeloproliferative Disorders - Lecture

Question 1

Myelodysplastic syndromes - general considerations

Answer 1

Disorders of the pluripotential stem cell

Characterized by ineffective hematopoiesis:
Proliferative defects
Differentiation abnormalities
Impaired apoptosis

Clinical picture…pancytopenia with hyperplastic marrow

Potential risk for development of acute leukemia

Question 2

Causes of Myelodysplastic syndrome

Answer 2

Chemo - breast, HL, NHL, acute leukemia

Alkylating agents—cyclophosphamide, ifosfamide, cisplatin, carboplatin, nitrogen mustard

Anthracycline antibiotics—Adriamycin, daunorubicin, epirubicin

Radiation - atomic bomb blast survivors, nuclear accidents, therapeutic

Petrochemical exposure

Question 3

Myelodysplastic syndrome: incidence and cytogenics (aka immunophenotype)

Answer 3

Mostly elderly (6th and 7th decade) 
Men and women equally affected

Partial or total loss of long arm of chromosome 5 or 7
Inversion of chromosome 16
Trisomy 8

Question 4

Clinical presentation of myelodyplasic syndrome

Answer 4

Constitutional symptoms—half are asymptomatic
Fatigue 
Pallor 
Bleeding 
Infection
Pancytopenia

Labs: elevated serum LDH, iron overload: increased serum ferritin but serum Fe and TIBC normal

Question 5

Refractory anemia with ringed sideroblasts (RARS)

Answer 5

Similarities to RA

Ringed sideroblasts in marrow precursors

Mitochondria laden with Fe encircling the nucleus of the erythroid precursors

No clear explanation for cause

Lowest risk of conversion to AML (10- 15%)

Pyridoxine deficiency: causes ringed sideroblasts in marrow - replace B6 for 6 mo then repeat marrow - if no improvement - pyridoxine resistant sideroblastic anemia (RARS)

Question 6

Clinical course of myelodysplastic syndrome

Answer 6

Poor prognosis - median survival 2 years, variable course

Adverse prognostic features:
Marrow blasts >5%
Platelets less than 100,000/uL
Hb less than 10g/dl
Neutrophils less than 2500/uL
Age > 60 yo

Poor prognosis:
Monosomy 7
Hypodiploidy
multiple abnormalities

Favorable:
5q- syndrome - beneficial responses to lenalidoamide

Question 7

Treatment of Myelodysplastic syndrome - supportive care

Answer 7

Supportive care:
Avoid medications that damage marrow
Aggressive treatment of infections
Transfuse PRBCs when symptomatic
Transfuse platelets only for bleeding or in preparation for surgery
Watch for iron overload-desferrioxamine (Desferal) or deferasirox (Exjade) if present

Hematinics
Supplemental vitamins not needed if chemical assays normal
B6 may be exception-trial of pyridoxine 100 mg/d for minimum of 6 months has been effective in some

Erythropoietin
May decrease or ameliorate transfusion requirement in some Serum EPO level > 500 predicts for poor response

Androgens
Variably effective and lots of side effects
Subset of patients with hypoplastic marrow may benefit
Reasonable to try if no other options exist

Corticosteroids
No beneficial effect and significant toxicity

Question 8

Treatment of Myelodysplastic syndrome - Low/Intermediate intensity therapy

Answer 8

Hypomethylating agents—azacitidine, decitabine cause hypomethylation (demethylation) of DNA and direct cytotoxicity on abnormal bone marrow hematopoietic cells

Lenalidomide—angiogenesis inhibitor for use in 5q- syndrome only

Question 9

Treatment of Myelodysplastic syndrome - high intensity therapy

Answer 9

AML induction-style treatment
Not as effective as de novo AML
Response rate=54% with 15% mortality rate at 30 days
Medial survival 13-15 months

Hematopoietic Stem Cell Transplantation
considered with MDS under 60 yo and have an HLA-matched sibling donor

significant chance of cure after allo-HCT in low and intermediate risk patients, transplant-related mortality and the relapse rate at five years are as high as 40%

Question 10

Myelofibrosis pathogenesis and presentation

Answer 10

triad: leukoerythroblastic anemia, poikilocytosis, splenomegaly

Increased reticulin deposition in marrow
Suspected to be 2ndary to increased platelet derived growth factor (PDGF) and other cytokines in marrow

Increased marrow megakaryocytes can be seen

Chronic stimulus to marrow fibroblasts that then make reticulin

Marrow architecture disrupted with subsequent mobilization of marrow stem cells to extramedullary sites (spleen, liver, lungs)

JAK2 mutations 45-65%, can be JAK -

Question 11

Myelofibrosis prognosis and treatment

Answer 11

Usually chronic but progressive
asymptomatic for years
Progressive pancytopenia and organomegaly indicate development of later stages of disease
Symptomatic its survive 1 year
Aloo-Stem cell transplant only curative tx

Tx:
Observation if asymptomatic
No therapy available for reversal of fibrosis
Some patients have been treated with BMT

Pancytopenia
Manage anemia with transfusion
EPO if serum EPO level less than 500 Transfuse platelets if bleeding occurs
Growth factors for neutropenia
Treat infections aggressively
-Overwhelming infection most common cause of death

Splenomegaly
Hydroxyurea variably effective-may be overly myelosuppressive
Radiation also helpful in some
In severe cases, splenectomy may help-can be dangerous - 30% mortality

Ruxolitinib: JAK inhibitor
-intermediate and high risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis